A critical component of an inflammatory response initiated by activated lymphocytes is attraction of macrophages and other immunological effector cells to the site of the reaction.
When a lymphocyte recognizes a foreign antigen, e.g., on the surface of cells infected with a virus or bacterium, the lymphocyte is not equipped to destroy microbial agents rapidly and efficiently. Elimination of pathogens and infected cells depends upon attraction and activation of immunological effector cells such as macrophages and neutrophils (Metchnikoff, E., 1893, Lectures on the Comparative Pathology of Inflammation, Kegan Paul, London; reviewed by Campbell, P., 1986, Immunol. Today 7:70-72). Activated T cells secrete a panel of peptides that induce other subsets of immunological cells to express their respective functions (Nabel, G., et al., 1981, Cell 23:19-28; Fresno, M., et a)., 1982, Cell 30:707-713). Definition of the genes that encode these peptides has depended on sensitive and reproducible assays that measure the biological activity of a particular peptide. This approach has identified several biologically active proteins produced by T cells (e.g., IL-2, IL-3, IL-4 and gamma-interferon).
The factors which stimulated T lymphocytes produce that induce various changes in macrophage function and physiology, including increases in effector cell functions (North, R. J., 1978, J. Immunol. 121:806; Rocklin, R. E., et al., 1980, Adv. Immunol. 29:56), have been termed macrophage-activating factors (MAF). Such MAF include gamma-interferon (Pace, J. L., et al., 1983, J. Immunol. 130:2011; Schultz, R. M. and Kleinschmidt, W. J., 1983, Nature (Lond.) 305:239; Svedersky, L. P., et al., 1984, J. Exp. Med. 159:812; Celada, A., et al., 1984, J. Exp. Med. 160:55-74). Activation of macrophage tumoricidal activity by gamma-interferon usually requires a second signal provided by endotoxin or lipopolysaccharide. In contrast, analysis of MAF activity in supernatant fluids of T cells indicates that tumoricidal activity may be mediated by material which does not require the presence of endogenous or added endotoxin, and may be serologically distinguishable from gamma-interferon (Boraschi, D., and Tagliabue, A., 1981, Eur. J. Immunol. 11:110-134; Andrew, P. W., et al., 1984, Eur. J. Immunol. 14:962; Kleinerman, E. S., et al., 1984, Cancer Res. 44:4470-4475; Lee, J., et al., 1986, J. Immunol. 136(4):1322-1328).
Evidence that activated lymphocytes produce soluble factors that might induce (Altman, L. C., et al., 1973, J. Immunol. 110:801) or inhibit (David, J. R., 1966, Proc. Natl. Acad. Sci. U.S.A. 56:72-77) macrophage migration has stimulated an extensive effort to define molecules responsible for these activities (Cameron, D. J. and Churchill, W. H., 1979, J. Clin. Invest. 63:977-984; Mantovani, A., et al., 1980, Int. J. Cancer 25:691-699; Steeg, P. S., et al., 1980, J. Exp. Med. 152:1734; for a review, see DeWeck, A. L., et al., eds., 1980, Biochemical Characterization of Lymphokines, Academic Press, New York). Tuftsin is a tetrapeptide (TKPR) that is the active fragment of leukophilic gamma-globulin, which stimulates migration and phagocytosis of macrophages and polymorphonuclear granulocytes (Najjar, V. A., 1974, Adv. Enzymol. 41:129-178; Najjar, V. A. and Nishioka, K., 1970, Nature 228:672; Fidalgo, B. V. and Najjar, V. A., 1967, Biochemistry 6(11):3386-3392; Fridkin, M., et al., 1977, Biochim. Biophys. Acta 496:203-211). Complement-derived factors have been shown to be chemotactic for mononuclear cells (Ward, P. A. and Newman, L. J., 1969, J. Immunol. 102:93), for eosinophils, and for neutrophils (Ward, P. A., 1969, Amer. J. Pathol. 54:121).
The RGD tripeptide marks a family of molecules that may induce changes in cellular motility and/or differentiation in a variety of cell types (reviewed by Ruoslahti, E. and Pierschbacher, M.D., 1986, Cell 44:517-518). The most well-studied member of this family is fibronectin, which has an RGD-containing subsequence similar to that present in Ap-1 (id.). Fibronectin, in conjunction with collagen or gelatin, can attach to macrophages, promoting an increase in surface receptors for immunoglobulin and for the C3b component of the complement proteins (Bevilacqua, M. P., et al., 1981, J. Exp. Med. 153:42-60; Wright, S. D. and Meyer, C., 1985, J. Exp. Med. 162:762-767).
There may be several instances of cell-cell interactions mediated by RGD-DGR complementarity. Studies of the association between MHC class I antigens and viruses have shown that Semliki Forest virus closely associates with a class I molecule in lipid bilayers (Helenius, A., et al., 1978, Proc. Natl. Acad. Sci. U.S.A. 75:3846-3850). Class I MHC molecules from different species contain a highly conserved DGR sequence. The glycophorin C molecule, which displays a DGR subsequence (Colin, Y., et al., 1986, J. Biol. Chem. 261:229-233), has been associated with penetration of Plasmodium merozoites into red blood cells and interaction with viruses and extracellular membrane (Pasvol, G., et al., 1984, Lancet 1:907-908).
Osteopontin (Oldberg, A., et al., 1986, Proc. Natl. Acad. Sci. U.S.A. 83:8819-8823; Franzen, A. and Heinegard, D., 1985, Biochem. J. 232:715-724; Franzen, A. and Heinegard, D., 1985, in Chemistry and Biology of Mineralized Tissues, Botler, W. T., ed., EBSCO, pp. 132-141) is a bone sialoprotein that contains an RGD cell-binding sequence, and is highly homologous to Ap-1. No immunological effector cell activity for osteopontin has been shown, and osteopontin is reported to be present solely in bone (id.). Osteopontin contains two additional repeats of a subsequence that is present only once in Ap-1, and contains a pentapeptide, YKQRA, absent from Ap-1. Furthermore, there are a total of 43 encoded amino acid residues which differ between Ap-1 and osteopontin, out of which 28 are nonconservative substitutions.
The extracellular matrix of bone marrow has been shown to contain an adhesive protein, termed haemonectin, of approximately 60,000 molecular weight and isoelectric point of about 4.5, which promotes selective attachment of cells of the granulocyte lineage (Campbell, A. D., et al., 1987, Nature 329:744-746). Haemonectin was not detectable in matrix preparations from spleen, mammary gland, or kidney (id.).